3HMN

Crystal structure of human Mps1 catalytic domain in complex with ATP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Biophysical and X-ray crystallographic analysis of Mps1 kinase inhibitor complexes.

Chu, M.L.Lang, Z.Chavas, L.M.Neres, J.Fedorova, O.S.Tabernero, L.Cherry, M.Williams, D.H.Douglas, K.T.Eyers, P.A.

(2010) Biochemistry 49: 1689-1701

  • DOI: https://doi.org/10.1021/bi901970c
  • Primary Citation of Related Structures:  
    3HMN, 3HMO, 3HMP

  • PubMed Abstract: 

    The dual-specificity protein kinase monopolar spindle 1 (Mps1) is a central component of the mitotic spindle assembly checkpoint (SAC), a sensing mechanism that prevents anaphase until all chromosomes are bioriented on the metaphase plate. Partial depletion of Mps1 protein levels sensitizes transformed, but not untransformed, human cells to therapeutic doses of the anticancer agent Taxol, making it an attractive novel therapeutic cancer target. We have previously determined the X-ray structure of the catalytic domain of human Mps1 in complex with the anthrapyrazolone kinase inhibitor SP600125. In order to validate distinct inhibitors that target this enzyme and improve our understanding of nucleotide binding site architecture, we now report a biophysical and structural evaluation of the Mps1 catalytic domain in the presence of ATP and the aspecific model kinase inhibitor staurosporine. Collective in silico, enzymatic, and fluorescent screens also identified several new lead quinazoline Mps1 inhibitors, including a low-affinity compound termed Compound 4 (Cpd 4), whose interaction with the Mps1 kinase domain was further characterized by X-ray crystallography. A novel biophysical analysis demonstrated that the intrinsic fluorescence of SP600125 changed markedly upon Mps1 binding, allowing spectrophotometric displacement analysis and determination of dissociation constants for ATP-competitive Mps1 inhibitors. By illuminating the structure of the Mps1 ATP-binding site our results provide novel biophysical insights into Mps1-ligand interactions that will be useful for the development of specific Mps1 inhibitors, including those employing a therapeutically validated quinazoline template.


  • Organizational Affiliation

    Wolfson Centre for Structure-Based Rational Design of Molecular Diagnostics, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity protein kinase TTK342Homo sapiensMutation(s): 0 
Gene Names: MPS1L1TTK
EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P33981 (Homo sapiens)
Explore P33981 
Go to UniProtKB:  P33981
PHAROS:  P33981
GTEx:  ENSG00000112742 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP33981
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ATP
Query on ATP

Download Ideal Coordinates CCD File 
B [auth A]ADENOSINE-5'-TRIPHOSPHATE
C10 H16 N5 O13 P3
ZKHQWZAMYRWXGA-KQYNXXCUSA-N
7PE
Query on 7PE

Download Ideal Coordinates CCD File 
C [auth A]2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL
C14 H30 O7
UKXKPKBTMYNOFS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.98α = 90
b = 104.95β = 90
c = 111.02γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-02-02
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description